Project Summary Multiple sclerosis (MS) is a chronic, demyelinating, neuroinflammatory disease typically affecting young adults, causing substantial morbidity and diminished quality of life. Although multiple disease-modifying immunomodulatory therapies are available for MS, disease manifestations and treatment response are highly variable and difficult to predict in patients. Current standard of care imaging techniques used to diagnose and monitor MS cannot provide early and specific molecular information regarding an individual?s immune signature in the central nervous system (CNS), thus limiting our ability to select the most appropriate therapy and obtain early predictors of response for any given patient. Hence there is a need for non-invasive molecular imaging strategies that provide real-time endpoints about specific immune cells and their functional phenotypes in MS patients. Myeloid cells are fundamental to the progression and remission of MS; activated macrophages and microglia are the predominant immune cells associated with acute and chronic-active CNS lesions. Unfortunately, existing imaging strategies for detecting activated microglia and macrophages lack specificity and cannot distinguish between beneficial (anti-inflammatory) and toxic (pro-inflammatory) immune responses. To address this limitation, we recently identified triggering receptor expressed on myeloid cells 1 (TREM1) as a highly specific, promising biomarker of toxic inflammation in a mouse model of MS, i.e., experimental autoimmune encephalomyelitis (EAE). TREM1 is a membrane receptor selectively expressed on myeloid lineage cells, known to exacerbate pro-inflammatory responses by synergizing with classical pattern recognition receptors. Our preliminary studies show elevated numbers of TREM1-expressing myeloid cells in the CNS of EAE mice (compared to controls) at very early stages of disease prior to the development of clinical symptoms. Moreover, the numbers of TREM1-positive myeloid cells are present at even higher levels in symptomatic mice, and appear to correlate with degrees of limb/tail paralysis. Here, we hypothesize that a novel positon emission tomography (PET) tracer we developed to target TREM1 can be used to detect and quantify in vivo myeloid-driven immune responses in rodent models of MS, and that TREM1-PET can accurately predict disease progression and response to therapies. We will test our hypothesis with the following specific aims: 1) To determine the relationship between TREM1-PET signal, disease severity, and peripheral markers of inflammation in two mouse models of MS, and 2) To assess the ability of TREM1-PET to predict and monitor outcomes after treatment with immunomodulatory therapeutics. We thus aim to establish the sensitivity and potential utility of our TREM1-PET tracer prior to clinical translation. This research promises to provide critical in vivo information about the role and time course of myeloid-driven immune responses in EAE and MS. Our proposed strategy using TREM1-PET could have far-reaching and significant impact as a molecular imaging technique for mapping toxic innate immune activation in a range of neurological diseases.